Abstract
MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223(-/y) mice presented with exacerbated myeloid- driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1 beta was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2(+) inflammatory monocytes and pharmacologic blockade of IL-1 beta or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3'untranslated region, phenocopied the characteristics of miR-223(-/y) mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1 beta release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation.
| Item Type: | Journal article |
|---|---|
| Faculties: | Medicine |
| Subjects: | 600 Technology > 610 Medicine and health |
| ISSN: | 0022-1007 |
| Language: | English |
| Item ID: | 52173 |
| Date Deposited: | 14. Jun 2018, 09:49 |
| Last Modified: | 04. Nov 2020, 13:30 |
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